Mechanisms and translation of lipid resuscitation

脂质复苏的机制和转化

• 批准号: 8333735
• 负责人: Israel Rubinstein
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333735
• 关键词: Accounting; Acute; Admission activity; Adrenergic beta-Antagonists; Aging; Alcohols; American; American Heart Association; Animal Model; Animals; Antidotes; Award; Binding; Blood capillaries; Blood flow; Brain; Bupivacaine; Bypass; Calcium Channel Blockers; Cardiac; Cardiopulmonary Resuscitation; Cardiotoxicity; Cardiovascular Physiology; Case Study; Cells; Cessation of life; Cocaine; Conduction Anesthesia; Cyclodextrins; Data Set; Development; Diffusion; Drug Prescriptions; Drug abuse; Drug toxicity; Elderly; Electron Microscopy; Emulsions; Endothelium; Fatty acid glycerol esters; Funding; Generic Drugs; Goals; Great Britain; Guidelines; Gunshot wound; Health; Heart; Histologic; Indium; Information Systems; Infusion procedures; Inpatients; Instruction; Intoxication; Intravenous Fat Emulsions; Ireland; Ischemia; Life; Lipids; Liposomes; Local Anesthetics; Measures; Medical; Metabolic; Military Personnel; Modification; Morbidity - disease rate; Myocardial; Neurologic; Neurologic Manifestations; Normal tissue morphology; Organ; Outcome; Overdose; Pharmaceutical Preparations; Phase; Physicians; Plasma; Play; Poisoning; Population; Prevalence; Process; Publishing; Radiolabeled; Rattus; Reaction Time; Recovery; Reperfusion Therapy; Resistance; Resuscitation; Risk; Signal Transduction; Site; Societies; Symptoms; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Toxin; Translating; Translations; Treatment Protocols; Tricyclic Antidepressive Agents; United States; Veterans; Work; aqueous; base; capillary; clinical practice; cocaethylene; cocaine overdose; cocaine use; effective therapy; fatty acid metabolism; improved; in vivo; inhibitor/antagonist; light microscopy; migration; nanomedicine; novel; novel strategies; particle; patient safety; prevent; radiotracer; research study; soy; uptake; vehicular accident

DESCRIPTION (provided by applicant): Work funded under the PI's previous VA Merit award has contributed directly to a novel and now widely accepted life-saving treatment for local anesthetic systemic toxicity (LAST). Intravenous lipid emulsion (ILE) resuscitation has also been used in many instances to rapidly reverse acute cardiac and neurological symptoms of toxicity caused by a wide range of lipophilic (fat soluble) medications. In many published case reports involving LAST or other overdoses, ILE was effective even after standard resuscitation measures had failed. ILE is now a principle element in treatment guidelines published by the American Society of Regional Anesthesia, the Anaesthetists of Great Britain and Ireland, the Resuscitation Council (UK) and was added to the most recent American Heart Association ACLS guidelines for treating LAST. Drug overdose is the second leading cause of accidental death in the United States contributing to 36,000 fatalities in 2007 placing it ahead of gunshot wounds and just behind motor vehicle accidents. Moreover, veterans are at particular risk given the prevalence of both illicit drug abuse and the difficulty for a geriatric population to adhere to instructions for such prescription drugs as long acting calcium channel blockers that can be potentially fatal in overdose. Notably, ILE has been used effectively in treating overdose of many common prescription medications (e.g. beta blockers, tricyclic antidepressants or calcium channel blockers) that can be highly resistant to standard resuscitation measures. Identifying the precise mechanism(s) underlying ILE holds the promise of improving its efficacy and providing an effective, generic antidotal treatment for a range of life-threatening toxic drug overdoses. However, the precise mechanisms of ILE are not well understood. The conventional explanation involves partitioning of the offending toxin into the newly created lipemic plasma phase, or 'lipid sink'. However, even this mechanism has not been tested rigorously in vivo. Moreover, we have observed that key aspects of ILE cannot be explained by the sink alone, indicating that other, less well-understood, mechanisms are also at play. We believe that ILE also directly benefits cardiovascular function and have confirmed in preliminary experiments that the infusion of lipid emulsion in the intact rat exerts positive effecs on cardiac contractility and aortic blood flow. We hypothesize that this results in part from direc, positive effects of fatty acid metabolism on cardiac function. Moreover, it is well-established tha tissue ischemia can cause intercellular endothelial gaps to expand, thereby allowing liposomes to migrate into the myocardial interstitium. Such passive targeting of lipid particles, essentially nano-medicine, will bypass the normal tissue barriers to diffusion of drug away from cells and diminish the response time to lipid signal effectors. We hypothesize that extravascular migration of lipid particles contributes to the overall efficacy of ILE in reversing cardiac drug toxicity. W propose studies to test the metabolic effects of ILE and transendothelial migration of lipid particles. Finally, we seek to improve the translation of ILE to cocaine-related toxicity and longer-lasting overdoses such as calcium channel blocker toxicity. Improved patient safety and outcomes from drug toxicity are the over-arching goals of this project.

描述（由申请人提供）： PI 之前的 VA 优异奖资助的工作直接促成了一种新颖且现已广泛接受的局部麻醉全身毒性 (LAST) 救生治疗方法。静脉脂质乳剂 (ILE) 复苏也已在许多情况下用于快速逆转由各种亲脂性（脂溶性）药物引起的急性心脏和神经系统毒性症状。在许多已发表的涉及 LAST 或其他过量用药的病例报告中，即使标准复苏措施失败，ILE 仍然有效。 ILE 现在是美国区域麻醉学会、英国和爱尔兰麻醉师协会、复苏委员会（英国）发布的治疗指南中的一个主要要素，并被添加到最新的美国心脏协会 ACLS 治疗 LAST 指南中。药物过量是美国意外死亡的第二大原因，2007 年导致 36,000 人死亡，排在枪伤之前，仅次于机动车事故。此外，由于非法药物滥用盛行，而且老年人很难遵守处方药（例如长效钙通道阻滞剂，过量服用可能致命）的说明，因此退伍军人面临特别的风险。值得注意的是，ILE 已被有效用于治疗许多常见处方药（例如 β 受体阻滞剂、三环类抗抑郁药或钙通道阻滞剂）的过量服用，这些药物对标准复苏措施具有高度抵抗力。确定 ILE 的精确机制有望提高其疗效，并为一系列危及生命的有毒药物过量用药提供有效的通用解毒治疗。然而，ILE 的确切机制尚不清楚。传统的解释涉及将有害毒素分配到新产生的脂血血浆相或“脂质汇”中。然而，即使这种机制也没有在体内经过严格的测试。此外，我们观察到 ILE 的关键方面不能仅用汇来解释，这表明其他不太了解的机制也在发挥作用。我们相信ILE也直接有益于心血管功能，并在初步实验中证实，在完整大鼠体内输注脂肪乳剂对心肌收缩力和主动脉血流产生积极影响。我们假设这部分是由于脂肪酸代谢对心脏功能的直接、积极影响所致。此外，众所周知，组织缺血会导致细胞间内皮间隙扩大，从而使脂质体迁移到心肌间质中。这种脂质颗粒的被动靶向，本质上是 纳米药物将绕过正常组织的药物扩散屏障，减少细胞对脂质信号效应器的反应时间。我们假设脂质颗粒的血管外迁移有助于 ILE 在逆转心脏药物毒性方面的总体功效。 W 提议进行研究来测试 ILE 的代谢影响和脂质颗粒的跨内皮迁移。最后，我们寻求改进 ILE 向可卡因相关毒性和更持久的过量用药（如钙通道阻滞剂毒性）的转化。改善患者安全和药物毒性结果是该项目的首要目标。